Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen's disease): clinicopathological spectrum with pathogenetic considerations

Abstract

Neurofibromatosis type 1 (NF-1, Recklinghausen disease) is the most common hereditary multitumor syndrome with an incidence at birth of approximately 1:3000. However, the significant variation in the expression of the disease not infrequently precludes early diagnosis. As a consequence of non-familiarity with their frequency and wide clinicopathological spectrum, gastrointestinal manifestations of NF-1 are seldom thought of in routine clinical practice and might thus be significantly under-recognized. Their heterogeneous spectrum ranges from localized microscopic proliferative lesions of autonomic nerves and interstitial cells of Cajal and diffuse microscopic ganglio/neuro/fibromatosis to grossly recognizable mass-forming neurofibromas and gastrointestinal stromal tumors (GIST). Furthermore, neuroendocrine neoplasms, particularly of the periampullary duodenum seem to be quite characteristic of this disease. Based on our own experience and the available literature, this review summarizes and discusses the clinicopathological spectrum of gastrointestinal manifestations of NF-1 including putative proliferative precursor lesions with emphasis on the differential diagnostic aspects of these disorders and their molecular pathogenesis. In addition, this review underlines the great value of specific gastrointestinal findings in uncovering undiagnosed or missed NF-1 cases.

Keywords: GIST; Gastrointestinal stromal tumor; NF-1; Neuroendocrine tumor; Neurofibromatosis; Recklinghausen disease.

Figure 1

A: Large duodenal GIST from a patient with undiagnosed NF-1. B: Histology showed a spindle cell GIST with multiple eosinophilic collagen deposits between tumor cells (skeinoid fibers) (H&E-stain, original magnification x400). Note nuclear variation typical of NF1-GIST.

Figure 2

A: duodenal somatostatinoma stained strongly with somatostatin (original magnification x200). B: diffuse interstitial cell of Cajal hyperplasia and a minute microscopic GIST focus in the duodenal wall surrounding somatostatinoma in A (CD117, original magnification x400).

Figure 3

B: A large retroperitoneal neurofibroma in NF-1 during surgical mobilization. No other gastrointestinal lesions have been detected during surgery in this patient. A: The resected tumor was surrounded by a smooth thin capsule. Histology revealed typical neurofibroma without evidence of malignancy.

Figure 4

Diffuse intestinal ganglio/neurofibromatosis in NF-1 highlighted by protein S100 stain (original magnification x200).

Figure 5

A: Diffuse interstitial cell of Cajal hyperplasia forming a thick layer encasing autonomic nerves of the Auerbach plexus adjacent to a larger GIST nodule (upper right). B: minute nodular focus of hyperplastic Cajal cells forming a microscopic tumorlet (lower right) from same patient (CD117 stain, original magnification x200).